Alkylene dioxy bis-benzylamines



nited States Patent ce 2759977 Patented Aug. 21, 19,56

acids. Examples of the inorganic acids suitable for the preparation of these acid addition salts are thecommon 2,759,977 mineral acids, e. g. .hydrochloric, nitric, sulfuric, and ALKYLENE DIOXY BISBENZYALAMINES I phosphoric ac1ds,;:eXamples of organic acids capable .of

a forming acid vaddition :salts with the bases of the inven- Koert Gerzon and Edwin R. Shepard, Indianapolis, Ind., tion are acetic, 'propionic, tartaric, benzoic, salicylic, assignors to Eli Lillyand Company, Indianapolis, Ind., maleic and the like acids. The acid addition salts of a corporation of Indiana the novel bases of the invention arereadily prepared by methods known to the art, as for example, .byinterreac- No D pphcatloqManh 1953 tion of stoichiometrically equivalent amounts of the se- Serial No. 344,668

lected base and an acid in mutual inert solvent solution.

6 Clalms- The preferred acid addition salts are the pharmaceutically useful salts, i. e., those salts which are not materially more toxic than the bases from which 'theyare derived This invention relates to substituted alkanes and more and which are suitable for incorporation into various particularly to u,w-bis-(oxybenzyldialkylamino) substipharmaceutical preparations useful for therapeutic aptuted alkanes, their acid addition salts and the processes plication.

for their preparation. The following examples show the preparation and The bases of the compounds ofthe invention can be physical properties of illustrative compounds of this inrepresented by the formula vention. R, R, EXAMPLE 1 R2 JR: l omllprh 1,2-ethane bis-(4'-oxybenzyl-methyl-n-hexylamine) dihydrochloride O(GH2),.0 wherein each R represents hydrogen or a lower ,alkoXy To a suspension of -8- 4 of ethylene glycol :radical, each R2 represents a lower alkyl radical, each my1p1 1enyl) ether, prepared according ,to the Rs repersents an alkyl radical having from three to ten method Nash Trav- Chlm- 66,

carbon atoms, and n represents an integer from ,2 to in 200ml- 9 ethanol Wefe cautlously fldded 2 6. The bases are solids which are insoluble in water and 30 of 5 P Palladium 011 h a The mlxture was soluble in most common organic solvents. The acid addihealed 011 a Steam a habout C r a out ten mmtion salts such as the mineral acid salts of the bases are utes- T0 hot mlxtufe Wradded -l generally somewhat Water-soluble but as .a rule are subof l 1eXY1am1I1e, q the u Contallllllg rstantially insoluble in the typical organic solvents. m la o ble schlifis base was hydrogenated usin an Thenew mid-substituted alkanes and theiracid addition Adams p s Wlth Fthe d of a heat q P- After salts are arnebicides and when administered orally or P- 0f f y Qg itlle reactlon m x-ture parenterally alone or in combination with pharmaceutical filtered 111116 9 v(10011118, j l-ethane extending media are useful for veterinary and human -PXY Y XY WJ formed 1 the n administration to bring about the control .or cure of ry lliz Was 'removed by filtration and dried n a amebiciinfections. 40 vacuumdeaiccator.

Broadly speaking, the new compounds areprepared :by The ,2- hane bis-(4 -oxybenzyl-n-hexylamine) thus condensing a suitably substituted l,2-bis-(4'-,forrnylp pared melted at about -95 9-9 Q, and was pure phenoxy) alkane with a primary 'alkylarnine to form enough for thf 11b$e lue11t reactlol} p an intermediate double iSchiifs base which is usually not To a wellstirred lee-cooled mixture of 20 ml. of 37 isolated, but is reduced with hydrogen in the presence of Pemflflt q q q e .SQIutiQlland fill-01590 a suitable catalyst to form the correspondingsecondary P n I 361d Were added 'g- 160- -J v0f allcylaminomethyl substituted bis phenoxyalkane. The P fl'fi 'L fi hane bi -i xr nzy w xy i in substituted 'bis1(al'kylaminomethy phenoxy) alkane is small portions A r e a di ion o the diami-n w s ialkylated '10 form :the vdesired idi-tertiar-y amine. The pl ed, IheSOI ltiDn Was heated fortone-half hour on following series of equations illustrating the preparation a steam bath and fi a y 1'9 W O I at efluxing' e of 1,2-ethane Ibis-1:4Foxybenzyl-methylm-butylamine) will Pe a u e- The reaction mixture was cooled, and poured serye jov-show jheacourse Offthe reactions, into about 200 ml. of ice water With Stirring. The water 2 "Pd catalyst (0mm, HCOOH As noted hereinabone, the .a,w-.-substituted alkanes of solution was made alkaline'by the addition of about 1-00 theinvent-ion contain two'basicmitrogenatoms:whichrcan ml. of :iced ,20 percent aqueous sodium hydoxide, with form acid addition salts with inorganic and organic stirring, The resulting prec pitate, consisting of 1,2

ethane bis-(4'-oxybenzyl-methyl-n-hexylamine) formed in the reaction, was removed by filtration and dried over postassium hydroxide in a desiccator. The dry material was recrystallized by dissolving it in warm Skellysolve B (a commercial petroleum ether), filtering and cooling to about C.

1,2 ethane bis-(4'-oxybenzyl-methyl-n-hexylamine) thus prepared melted at about 61-62 C.

Analysis.-Calculated for C30H48N202Z Found: N, 5.98.

Dry hyrogen chloride gas was passed through a solution of 9.4 g. of 1,2-ethane bis-(4-oxybenzyl-methyl-nhexylamine) in 100 ml. of acetone until 1.5 g. of hydrogen chloride had been absorbed. The acetone solution was cooled in ice, and the precipitate, comprising the dihydrochloride salt of 1,2-ethane bis-(4'-oxybenzylmethyl-n-hexylamine) was removed by filtration and recrystallized from a mixture of ethanol and ether.

1,2-ethane bis-'(4'-oxybenzyl-methyl-n-hexylamine) dihydrochloride thus prepared melted at about 210-211 C.

Analysis-Calculated for CsoI-LrsNzOz-ZHCl: C, 66.54; H, 9.38; Cl, 13.09. Found: C, 66.57; H, 9.53; Cl, 13.33.

EXAMPLE 2 LEI-propane bis-(4-0xybenzyl-methyl-n-hexylamine) dihydrochloride To a suspension of 14.2 g. of trimethylene glycol bis- (4'-formylphenyl) ether, prepared according to the method of Neish, Rec. Trav. Chim. Pays-Bas, 66, 433, (1947), in 100 ml. of ethanol was cautiously added to 1 g. of 5 percent palladium on charcoal. The suspension was heated on a steam bath to about 60 C. for about ten minutes, and 10.1 g. of n-hexylamine were added to the warm suspension. The mixture was hydrogenated in an Adams apparatus, and the solution was filtered hot to remove the catalyst. On cooling, the 1,3-propane bis-'(4-oxyoenzyl-n-hexylamine) formed in the reaction crystallized out, and was removed by filtration and recrystallized from ethanol solution. The 1,3-propane bis-(4'-oxybenzyl-nhexylamine) thus prepared was methylated using formaldehyde and formic acid according to the procedure in Example 1. The 1,3-propane bis-(4-oxybenzyl-methyl n-hexylamine) which formed was removed from the reaction mixture by filtration and dried. 1,3-propane bis-(4'- oxybenzyl-methyl-n-hexylamine) thus prepared is a lowmelting solid.

The 1,3-propane bis-'(4'-oxybenzyl-methyl-n-hexylamine) was converted to its dihydrochloride salt by the same process as set forth in Example 1. 1,3-propane bis- (4-oxybenzyl-methyl-n-hexylamine) dihydrochloride thus prepared melted at about 171-172 C.

Analysis.-Calculated for Cs1H5oN2O2-2HCl: C, 66.97; H, 9.43; Cl, 12.76. Found: C,'66.80; H, 9.49; Cl. 12.70.

EXAMPLE 3 1,2-ethane bis-(4-0xybenzyl-methyl-n-heptylamine) dihydrochloride bis-(4-oxybenzyl-n-heptylamine) obtained was recrystallized from ethanol, and melted at about 93-94 C.'

Anaylsis. Calculated for C30H48N2022 N, 5.97. Found: 5.78.

Methylation of 1,2-(4'-oxybenzyl-n-heptylamine) with formic acid-formaldehyde mixture according to the procedure of Example 1 produced 1,2-ethane bis-(4-oxybenzylmethyl-n-heptylamine) which after recrystallization from ether melted at about 49-5 0 C.

Analysis. Calculated for CzzHszNzOz: N, 5.64. Found: N, 5.80.

10 g. of 1,2-ethane bis-(4'-oxybenzyl-methyl-n-heptyl- I amine) were dissolved in 200 ml. of anhydrous ether and dry hydrogen chloride gas was passed through the ether solution until no further precipitate occurred. The dihyphenyl ether),

drochloride salt of 1,2-ethane bis-(4-ozybenzyl-rnethyln-heptylamine) thus prepared melted at 217-218 C. after recrystallization from ethanol-ether mixture.

Analysis.Calculated for C32H52N2O2-2HC1: C, 67.47; H, 9.35. Found: C, 67.31; H, 9.58.

EXAMPLE 4 1,2-ethane bis (4'-0xy-3'-methoxybenzyl-methyl-nhexylamine) A mixture of 123.5 g. of ethylene bromide,,,220 g. of vanillin, 500 ml. of water and 500 ml. of methylcellosolve was brought to refluxing while stirring, and a solution of 52.5 g. of sodium hydroxide in 250 ml. of water was added in the course of about one hour. Refiuxing and stirring were continued for about four hours, and the reaction mixture was cooled, whereupon a precipitate of 1,2-bis-(4'-forrnyl-2methoxyphenoxy) ethane formed, and was filtered off, washed with water and dried. Upon recrystallization from methylcellosolve, 1,2-bis-(4-formyl- 2-methoxyphenoxy) ethane melted at about 186-187 C.

A solution of 16.1 g. of 1,2-bis-(4'-formyl-2-methoxyphenoxy) ethane and 10.1 g. of n-hexylamine in 200 ml. of boiling ethanol was refluxed for about one-half hour and filtered while hot. On cooling, the double Schiifs base formed in the reaction crystallized and was removed by filtration. On recrystallization from ethanol the double Schifls base melted at about 93-94 C.

Analysis. Calculated for Gaol-144N204! Found: N, 5.26.

To a solution of 20 g. of the double Schiifs base in 200 ml. of ethanol were added 2 g. of 5 percent palladium on charcoal. The mixture was hydrogenated in an Adams apparatus with the aid of an infrared heating lamp. The reaction mixture was filtered hot to remove the catalyst, and on cooling, the 1,2-ethane bis-(4'-oxy-3-methoxybenzyl-n-hexylamine) formed in the reaction crystallized and was removed by filtration. After recrystallization from a mixture of ethyl acetate and petroleum ether, the 1,2 ethane bis-(4-oxy 3-methoxybenzyl-n-hexylamine) melted at about 7 3-75 C.

Analysis. Calculated for C30H48N204! N, 5.59. Found: N, 5.34.

The 1,2-ethane bis-(4-oxy-3-methoxybenzyl-n-hexylamine) was methylated using aqueous formaldehyde and formic acid according to the procedure of Example 1. The 1,2-ethane bis-(4-oxy-3-methoxybenzyl-methyl-nhexylamine) thus prepared melted at about 61-62 C.

The dihydrochloride salt of 1,2-bis-(4'-oxy-3-methoxybenzyl-methyl-n-hexylamine) was prepared according to the procedure set forth in Example 1. After recrystallization from acetone the 1,2-bis-(4-oxy-3-rnethoxybenzyl-methyl-n-hexylamine) dihydrochloride-monohydrate thus prepared melted at about 222-224" C.

Analysis.-Calculated for C3zH5zN2O4-2HCl-H2O: C, 62.10; H, 9.05; Cl, 11.45. Found: C, 62.00; H, 9.03; CI, 11.61.

EXAMPLE 5 1,2-ethane bis-(4-oxybenzyl-methyl-2-n-heptylamine) A mixture of 13.5 g. of ethylene glycol bis-(4-formyl- 11.5 g. of Z-aminoheptane and 200 ml. of ethanol was refluxed 'forabout one-half hour and filtered hot. On cooling, the intermediate double Schifis base crystallized and was removed by filtration. After recrystallization from petroleum ether, the double Schiifs base melted at about 96-98 C.

Analysis-Calculated for: Cad-144N202: N, 6.04.

Found: N, 6.04.

The intermediate double Schifisbase was dissolved in about ml. of ethanol and 2 g. of 5 percent palladium on charcoal catalyst were added. The mixture was hydrogenated in an Adams apparatus. The reaction mixture was filtered to remove the catalyst and on cooling, the 1,2-ethane bis-(4-0xybenzyl-2"-n-hepty1- amine) formetl cl ystall'izedand was removed hy "filtration. On recrystallization from petroleum ether, 1,2- ethane bis-(4'-oxybenzyl-2"-n-heptylamine) melted at about 58-60 C.

Analysis.-Calculated for CaoH4sNzO2: Found: N, 5.93.

The l,2-ethane bis-(4'-oxybenzyl-2 n heptylamine) was methylated by means of formaldehyde .and formic :acid accordingto #the procedure described in Example The dihydrochloride salt or Iil,2ethane .bis-.(4'eoxy' benzyl-methyl-2"-n-heptylamine') was prepared according to the procedure of Example 1.

EXAMPLE 6 1,2-ethane bis-(4'-oxybenzyl-methyl-n-hexylamine) sulfate.

To a solution of 4.68 g. (0.01 mol.) of 1,2-ethane bis- (4'-oxybenzyl-methyl-n-hexylamine) prepared according to the procedure of Example 1, in 50 ml. of cellosolve are added ml. of M/1 H2504. The solution is thoroughly stirred, and evaporated to dryness in vacuo.

The residue from evaporation is 1,2-ethane bis-(4- oxybenzyl-methyl-n-hexylamine) sulfate.

Similarly, the nitric, acetic, propionic and benzoic acid addition salts of 1,2-ethane bis-(4'-oxybenzyl-methyl-nhexylamine) are prepared by the addition of stoichiometrically equivalent amounts of nitric, acetic, propionic and benzoic acids to a solution of 1,2-ethane bis-(4-oxybenxyl-methyl-n-hexylamine) followed by evaporation of the solvent.

1,3-propane bis-(4'-oxybenzyl-methyl-n-hexylamine), 1,2-ethane bis-(4'-oxybenzyl-methyl-n-heptylamine), 1,2- cthane bis-(3-rnethoxy-4'-oxyhenzyl methyl n hexyl amine) and 1,2-ethane bis-(4'-oxybenzyl-methyl-2"-nheptylamine) are substituted for 1,2-ethane bis-(4'-oxybenzyl-methyl-n-hexylamine) in the forgoing procedures. The sulfate, dinitrate, diacetate, dipropionate, and dibenzoate salts of the named compounds, respectively, are obtained.

EXAMPLE 7 The procedure of Example 1 was followed except that n-butylamine was used instead of n-hexylamine.

1,2-ethane bis-(4'-oxybenzyl-methyl-n-butylamine) thus prepared melted at about 52-53 C.

Analysis.-Calculated for C2sH4oN2O2: N, 6.79. Found: N, 6.48.

EXAMPLE 8 The procedure of Example 1 was followed, except that n-pentylamine was used instead of n-hexylamine.

EXAMPLE 9 The procedure of Example 1 was followed except that nwctylarn-ine was used instead of n-hexylamine.

The dihydrochloride salt of 1,2-ethane bis-(4'-oxybenzyl-methyl-n-octylamine) melted at about 214- 215 C.

Ana lysis.Calculated for C34H56N202'2HC1! N, 4.69. Found: N, 4.72.

EXAMPLE 10 Example 1 was repeated, using n-decylamine instead of n-hexylamine.

1,2-ethane bis-(4-oxybenzyl-methyl-n-decylamine) dihydrochloride thus prepared melted at about 223-224 C.

Analysis.-Calculated for C3sHs4N2Oz-2HC1: C, 69.80; H, 9.87. Found: C, 69.78; H, 10.03.

EXAMPLE 11 The method of Example 1 was carried out, using the corresponding quantity of 1,4-tetramethylene glycol bis- (4'-forrnylphenyl) ether, prepared according to the meth- 0d of Neish, Rec. Trav. Chim. Pays-Bas, 66 433 (1947), instead of ethylene glycol bis-(4-formylphenyl) ether.

1,4-butane bis-(4'-oxybenzyl-methyl-n-hexylamine) thus prepared melted at about 49-50 C.

Analysis.-Calculated for C32H52N2O2: Found: N, 5.83.

The dihydrochloride salt of 1,4-butane bis-(4'-oxy benzyl-methyl-n-hexylamine) melted at about 198-199 C.

Analysis.Calculated for CszHazNzOz-ZHCI: C,67.54; H, 9.52; Cl, 12.75. Found: C, 67.67; H, 9.25; Cl, 12.38.

We claim:

1. A member of the group consisting of a base and its acid addition salts, said base being represented by the formula:

wherein R1 represents a member of the group consisting of hydrogen and lower alkoxy radicals, R2 represents a lower alkyl radical, R3 represents a member of the group consisting of alkyl radicals having from 3 to 10 carbon atoms, and n represents an integer from 2 to 6.

2. 1,2-ethane bis-(4'-oxybenzyl-methyl-n hexylamine) represented by the formula:

1,2-ethane bis-(4'-oxybenzyl-methyl n pentylamine) thus prepared melted at about 5253 C.

3. 1,3-propiane bis-(4'-oxybenzyl-methyl-n-hexylamine) represented by the formula:

Analysis-Calculated for C2aH44N2O2: N, 6.36.

Found: N, 6.15.

4. 1,2-ethane bis-(4-oxybenzyl-methyl-n-heptylamine) represented by the formula:

8 5. 1,2-ethane bis-(4'-oxy-3-methoxybenzy1 methyl-n- 6. 1,2 ethane bis-(4'-oxybenzy1-methy1-2"-n-hepty1ahexylamine) represented by the formula:

0 CH; 0 CH References Cited in the file of this patent FOREIGN PATENTS 104,522 Sweden May 19, 1942 223,161 Switzerland Nov. 16, 1942 

1. A MEMBER OF THE GROUP CONSISTING OF A BASE AND ITS ACID ADDITION SALTS, SAID BASE BEING REPRESENTED BY THE FORMULA: 